Abstract This application is being submitted to PA-18-591 in accordance with NOT-OD-18-195. The goal of this administrative supplement is to expand our currently funded research involving Down syndrome (DS) as a model of neurodegeneration and to better understand potential mechanisms for enhanced xenobiotic toxicity observed in this population. Our research (R01 ES027593) is aimed at testing the working hypothesis that environmental exposures contribute to cognitive phenotype variability in DS via disrupted thiol redox signaling and control due to enhanced basal levels of cellular stress and mitochondrial dysfunction. In addition to the cellular stress that we have observed in DS using patient-derived cell lines, our laboratory and others have found that cells from DS individuals display enhanced toxicity to a variety of agents. As DS affects the entire body, cellular stress impacting hepatocytes could alter efficiency and specificity of metabolic enzymes within this cell type, providing mechanistic insight into the sensitivity of the DS population to xenobiotics and pharmaceuticals. Therefore, an additional factor that may contribute to enhanced toxicity in DS is the distinct possibility that xenobiotic biotransformation systems in DS may differ considerably compared to euploid individuals. Furthermore, xenobiotic biotransformation processes can both eliminate or enhance the toxicity of xenobiotics and pharmaceutical agents; thus, it is vital to understand any differences in biotransformation in the DS population, which will better inform the scientific community as to potential adverse events pertaining to both xenobiotic and pharmaceutical agent exposure. Due to these observations it is hypothesized that, because of alterations in cellular proteostasis and redox status, both of which can impact protein expression and function, DS individuals will display altered hepatic xenobiotic biotransformation compared to euploid controls. A single aim has been proposed that will investigate this innovative concept and will determine alterations in basal expression, protein abundance and activity of a variety of xenobiotic biotransformation enzymes. Also, the four xenosensor transcription factors will also be assessed for any differences in activation, gene inducibility, and the impact that the fungicide maneb has on induction of the xenobiotic response. Finally, as per the Notice, NOT-OD-18-195, the research proposed here and within our currently funded R01 (R01 ES027593) are completely appropriate and data generated are likely to translate into new therapeutic approaches (component 1 of INCLUDE project objectives). Given that 100% of DS patients have cognitive deficits, understanding the mechanistic differences in cell death in this population is important. Also, since the phenotype of DS individuals at birth is a predictor of the severity of pathologies in later adult years, this research will begin to answer the question that pertains to whether phenotypic variations at birth and later life prognosis can be predicted from cell viability and vulnerability.